气候变化领域集成服务门户(CCPortal): Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants

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DOI	10.1073/pnas.2022403118
	Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants
	Moghadamchargari Z.; Shirzadeh M.; Liu C.; Schrecke S.; Packianathan C.; Russell D.H.; Zhao M.; Laganowsky A.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also allosterically modulated by an active Ras (Ras–GTP). However, it remains poorly understood how oncogenic Ras mutants interact with SOS and modulate its activity. Here, native ion mobility–mass spectrometry is employed to monitor the assembly of the catalytic domain of SOS (SOScat) with KRas and three cancer-associated mutants (G12C, G13D, and Q61H), leading to the discovery of different molecular assemblies and distinct conformers of SOScat engaging KRas. We also find KRasG13D exhibits high affinity for SOScat and is a potent allosteric modulator of its activity. A structure of the KRasG13D•SOScat complex was determined using cryogenic electron microscopy providing insight into the enhanced affinity of the mutant protein. In addition, we find that KRasG13D–GTP can allosterically increase the nucleotide exchange rate of KRas at the active site more than twofold compared to KRas–GTP. Furthermore, small-molecule Ras•SOS disruptors fail to dissociate KRasG13D•SOScat complexes, underscoring the need for more potent disruptors. Taken together, a better understanding of the interaction between oncogenic Ras mutants and SOS will provide avenues for improved therapeutic interventions. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer \| Ras proteins \| native mass spectrometry \| Ras-SOS
语种	英语
scopus关键词	guanosine triphosphatase; K ras protein; Ras protein; SOS protein; allosterism; Article; binding affinity; catalysis; complex formation; controlled study; cryoelectron microscopy; G12C gene; G13D gene; ion mobility spectrometry-mass spectrometry; nucleotide transport; oncogene; priority journal; protein assembly; protein conformation; protein domain; protein function; protein protein interaction; protein structure; Q61H gene
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180190
作者单位	Department of Chemistry, Texas A&M University, College Station, TX 77843, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, United States
推荐引用方式 GB/T 7714	Moghadamchargari Z.,Shirzadeh M.,Liu C.,et al. Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants[J],2021,118(12).
APA	Moghadamchargari Z..,Shirzadeh M..,Liu C..,Schrecke S..,Packianathan C..,...&Laganowsky A..(2021).Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Moghadamchargari Z.,et al."Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).